ART-associated Tuberculosis Research Articles

Despite antiretroviral therapy (ART) rollout, most cases of tuberculosis among people with HIV in Adama, Ethiopia, occur before ART initiation

ABSTRACT Introduction Although antiretroviral therapy (ART) leads to reduced tuberculosis (TB) incidence in people with HIV (PWH), ART recipients remain at higher risk of TB compared to HIV-seronegative people. With accelerated ART rollout in sub-Saharan Africa, increasing proportions of TB cases among PWH in people receiving long-term ART have been reported. Objective To determine TB notifications among PWH by ART status in a mainly urban uptake area in Ethiopia during an 8-year period in connection to the introduction of the ‘test-and-treat’ strategy for HIV. Methods PWH were identified from registers at health facilities providing ART in Adama and surrounding areas, Ethiopia 2015–2022. Annual TB notifications were compared over time. PWH within TB were categorized by ART status at the time of TB diagnosis (pre-ART TB: TB diagnosed before or ≤6 months after starting ART; ART-associated TB: TB diagnosed >6 months after starting ART). Results Among a total of 8,926 PWH, 993 had been diagnosed with TB (11.1%); mean age 40.0 years [SD 11.8], 53.5% were men). Throughout the study period, most TB cases had been notified before ART initiation (617/993; 62.1%). ART-associated TB cases constituted a mean of 37.4% (range 23.8%–44.2%) of all TB cases among PWH annually. Median time from ART initiation to TB diagnosis among ART-associated TB was 6.0 years. Conclusion TB notifications among PWH in this area did not decrease 2015–2022, implying persistently high risk of TB among PWH in this setting. Most TB cases occurred in ART-naïve persons, illustrating late HIV diagnosis in this population.

Added Value of Long-Term Cytokine Release Assays to Detect Mycobacterium tuberculosis Infection in HIV-Infected Subjects in Uganda.

To investigate whether mycobacterial antigen-induced cytokine secretions are helpful in detecting Mycobacterium tuberculosis (Mtb) infection in a cohort of HIV-infected patients living in a country with a high burden of Mtb and HIV infections, and to determine their predictive value for the development of tuberculosis (TB)-associated immune reconstitution inflammatory syndrome. A total of 352 HIV-infected patients (186 with active TB) were prospectively enrolled when initiating antiretroviral therapy (ART). Sequential blood samples were collected during the first 6 months of ART. Eighty-three HIV-uninfected subjects (39 with active TB) were enrolled as controls. The concentrations of 13 cytokines were measured in supernatants from blood mononuclear cells in vitro stimulated with purified protein derivative (PPD), heparin-binding hemagglutinin (HBHA) or early secreted antigen-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), and results were compared with those of tuberculin skin tests (TST). The best detection of Mtb infection was achieved by ESAT-6/CFP-10-induced interferon-γ concentrations, but results were often negative for patients with CD4 T-cell counts <50 per cubic millimeters. Patients with active TB were identified by high ESAT-6/CFP-10-induced interleukin-6. Conversions of interferon-γ-release assays (IGRA) and TST occurred under ART, and combined TB and antiretroviral treatments of coinfected patients resulted in a decrease of ESAT-6/CFP-10-induced and an increase of HBHA-induced interferon-γ responses. No Mtb antigen-induced cytokines allowed us to predict TB-immune reconstitution inflammatory syndrome or ART-associated TB. In Uganda, ESAT-6/CFP-10-IGRA is better in detecting Mtb infection than TST and, when combined with an HBHA-IGRA, could help to evaluate anti-TB treatment success.

Impact of Xpert MTB/RIF on Antiretroviral Therapy-Associated Tuberculosis and Mortality: A Pragmatic Randomized Controlled Trial.

Introduction. GeneXpert® MTB/RIF (Xpert) is now widely distributed in high human immunodeficiency virus (HIV)/tuberculosis (TB)-burden countries. Yet, whether the test improves patient-important outcomes within HIV treatment programs in limited resource settings is unknown.Methods. To investigate whether use of Xpert for TB screening prior to initiation of antiretroviral treatment (ART) improves patient-important outcomes, in a pragmatic randomized controlled trial we assigned 424 patients to Xpert or fluorescence sputum smear microscopy (FM) at ART initiation. The primary endpoint was a composite of 3-month mortality and ART-associated TB.Results. There was no difference in overall TB diagnosis at ART initiation (20% [n = 43] Xpert vs 21% [n = 45] FM; P = .80), with most patients in both groups treated empirically. There was no difference in time to TB treatment initiation {5 days (interquartile range [IQR], 3–13) vs 8 days [IQR, 3–23; P = .26]} or loss to follow-up (32 [15%] vs 38 [18%]; P = 0.38). Although a nonsignificant reduction in mortality occurred in the Xpert group (11 [6%] vs 17 [10%]; 95% CI, −9% to 2%; P = .19), there was no difference in the composite outcome (9% [n = 17] Xpert vs 12% [n = 21] FM; difference −3%; 95% CI, −9% to 4%).Conclusions. Among HIV-infected initiating ART, centralized TB screening with Xpert did not reduce the rate of ART-associated TB and mortality, compared with fluorescence microscopy.

Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery

To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution.

Tuberculosis After Commencing Antiretroviral Therapy for HIV Infection Is Associated With Elevated CXCL9 and CXCL10 Responses to Mycobacterium tuberculosis Antigens

Commencing antiretroviral therapy (ART) in human immunodeficiency virus-infected patients with treated or unrecognized Mycobacterium tuberculosis disease may trigger tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB). We have shown that whole-blood interferon-gamma release assays may aid in the prediction and diagnosis of ART-TB. Here, we investigate interferon-gamma-inducible chemokines CXCL9 and CXCL10. CXCL9 and CXCL10 responses to region of difference 1 (RD1) antigens and purified protein derivative (PPD) were assayed in plasma from whole-blood cultures collected before and after 4, 12, and 24 weeks of ART from 15 TB-IRIS cases, 11 ART-TB cases, and matched controls. Relative to matched controls, ART-TB cases had elevated CXCL10 responses to RD1 antigens pre-ART (P = 0.02) and to PPD and RD1 antigens over 24 weeks of ART (P ≤ 0.02 and P ≤ 0.03). In contrast, TB-IRIS cases had higher CXCL10 responses to RD1 antigens before and after 4 weeks of ART only (P = 0.04 for both). CXCL9 responses to PPD and RD1 antigens were similar but less pronounced in ART-TB cases and did not differ between TB-IRIS cases and controls. CXCL10 responses to RD1 antigens performed as well as, or better than, IFN-γ responses in the prediction and diagnosis of ART-TB. Tuberculosis after commencing ART is associated with increased CXCL10 and, to a lesser extent, CXCL9 responses to M. tuberculosis antigens. Assessment of antigen-induced CXCL10 responses to RD1 antigens may assist in the prediction and diagnosis of ART-TB.

Predictors of tuberculosis in first 6 months after initiation of antiretroviral therapy: a case-control study.

In Africa, 10% of human immunodeficiency virus (HIV) infected adults starting antiretroviral therapy (ART) die within the first year, and tuberculosis (TB) is the leading cause of death. To investigate the predictors of ART-associated TB at an adult HIV clinic in Tanzania. In this nested case-control study, adults starting ART were screened for TB according to the World Health Organization protocol. Those not diagnosed with TB were observed for 6 months. Patients diagnosed with TB were defined as cases, and controls were selected from among the patients who did not develop TB using incidence density matching. Among the 2514 HIV-positive adults in our cohort, 72 (3%) were diagnosed with TB during the first 6 months of ART. By multivariate analysis, baseline characteristics predictive of TB were cough, fever and night sweats; 76% (55/72) of the cases had at least one of these symptoms at the time of starting ART. Overall, 75% of the patients who developed TB during the first 6 months of ART had TB symptoms at the time of starting ART. Improved TB diagnostics and/or better strategies for empirical anti-tuberculosis treatment are needed for patients with symptoms of TB at ART initiation.

Increased Plasma CXCL10 May be a Marker of Increased Risk of Immune Restoration Disease Associated With Nonviral Pathogens

Increased Plasma CXCL10 May be a Marker of Increased Risk of Immune Restoration Disease Associated With Nonviral Pathogens

Predictors of antiretroviral treatment-associated tuberculosis in Ethiopia: a nested case-control study

Little is known about the predictors of antiretroviral treatment (ART)-associated tuberculosis (TB) in developing nations. The objective of this study was to determine predictors of ART-associated TB in adults with HIV infection at Jimma University Hospital, Ethiopia. A nested case-control study was conducted in October 2009. The study population consisted of adults with HIV infection (aged >14 years) who developed active TB in the first six months since ART initiation and controls that did not develop active TB. Data were collected using a structured and pretested questionnaire. Cox proportions hazards analysis was done to determine predictors of ART-associated TB. A total of 357 patients (119 cases and 238 controls) participated in the study. After six months of follow-up, cumulative incidence of ART-associated TB was 5.2% (123/2355). Forty (33.6%) cases were lost to follow-up after they developed ART-associated TB and 11 (9.2%) died. Fifty-one (21.4%) controls interrupted ART and 11 (4.6%) died. A CD4 lymphocyte count increase >0.5/μL/day (adjusted hazard ratio [AHR] = 19.80, 95% confidence interval [CI]: 9.52, 41.12, P < 0.001), a base-line CD4 lymphocyte count <200 cells/μL (AHR = 9.59, 95% CI: 2.36, 39.04, P = 0.002), World Health Organization (WHO) clinical stage 3 or 4 (AHR = 3.04, 95% CI: 1.62, 5.69, P < 0.001), night sweats during ART initiation (AHR = 1.53, 95% CI: 1.06, 2.21, P < 0.001) and high ART adherence (AHR = 1.30, 95% CI: 1.13, 1.50, P < 0.001) were independent predictors of ART-associated TB. HIV-infected adults with these risk factors should be followed cautiously for the development of ART-associated TB. Good ART adherence and a good immunological response during ART were associated with ART-associated TB, most likely because of an immune reconstitution inflammatory syndrome unmasking the TB.

Antiretroviral Treatment-Associated Tuberculosis in a Prospective Cohort of HIV-Infected Patients Starting ART

Commencement of antiretroviral treatment (ART) in severely immunosuppressed HIV-infected persons is associated with unmasking of subclinical disease. The subset of patients that are diagnosed with tuberculosis (TB) disease while on ART have been classified as ART-associated TB. Few studies have reported the incidence of ART-associated TB and unmasking TB-IRIS according to the International Network for the Study of HIV-Associated IRIS (INSHI) consensus definition. To determine the incidence and predictors of ART-associated TB, we screened 219 patients commencing ART at the Infectious Diseases Clinic in Kampala, Uganda for TB by symptoms, sputum microscopy, and chest X-rays and followed them for one year. Fourteen (6.4%) patients were diagnosed with TB during followup. Eight (3.8%) patients had ART-associated TB (incidence rate of 4.3 per 100 person years); of these, three patients fulfilled INSHI criteria for unmasking TB-associated IRIS (incidence rate of 1.6 per 100 person years). A body mass index of less than 18.5 kg/m2 BMI (HR 5.85 95% CI 1.24–27.46, P = .025) and a C-reactive protein greater than 5 mg/L (HR 8.23 95% CI 1.36–38.33, P = .020) were risk factors for ART-associated TB at multivariate analysis. In conclusion, with systematic TB screening (including culture and chest X-ray), the incidence of ART-associated TB is relatively low in settings with high HIV and TB prevalence.

Mediators of Innate and Adaptive Immune Responses Differentially Affect Immune Restoration Disease Associated withMycobacterium tuberculosisin HIV Patients Beginning Antiretroviral Therapy

Initiation of antiretroviral therapy (ART) in human immunodeficiency virus patients with treated or unrecognized Mycobacterium tuberculosis infection may result in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB), respectively. Both conditions appear to be immune restoration disease but their immunopathogenesis is not completely understood. Chemokines and cytokines produced by the innate immune system (CCL2, CXCL8, CXCL9, CXCL10, and interleukin 18 [IL-18]) were assayed in plasma from unstimulated whole blood cultures obtained from 15 TB-IRIS case patients, 11 ART-TB case patients, and matched control participants over 24 weeks of ART. When compared with control participants, levels of IL-18 and CXCL10 were higher in TB-IRIS case patients (P = .002 and .006, respectively), whereas CCL2 was lower (P = .006). IL-18 level was higher in ART-TB case patients (P = .002), but CXCL10 was only marginally higher (P = .06). When TB-IRIS case patients were compared with ART-TB case patients, IL-18 was higher in ART-TB (P = .03), whereas CXCL10 was higher in TB-IRIS (P = .001). Using receiver operating characteristic curves, pre-ART levels of CCL2, CXCL10, and IL-18 were predictive of TB-IRIS and additive to IFN-γ responses. Perturbations of the innate immune response to M. tuberculosis before and during ART may contribute to the immunopathology of TB-IRIS, whereas elevated IL-18 alone suggests adaptive immune responses predominate in ART-TB. These findings may have implications for therapy in TB-IRIS.

Immunopathogenesis and Diagnosis of Tuberculosis and Tuberculosis‐Associated Immune Reconstitution Inflammatory Syndrome during Early Antiretroviral Therapy

In many settings, the benefits of antiretroviral therapy (ART) are reduced by the high early incidence of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). We used tuberculin skin testing and the QuantiFERON-TB Gold In-Tube assay to investigate cellular immune responses to purified protein derivative (PPD) and region of difference 1 (RD1) antigens during the first 24 weeks of ART. TB-IRIS and ART-associated tuberculosis occurred in 15 of 75 (20%) and 11 of 231 (4.8%) participants at risk, respectively. Greater increases in interferon gamma (IFN-gamma) and skin test responses to PPD were seen at week 24 and 12 in participants with TB-IRIS (P< or = .04), respectively. Raw IFN-gamma responses to RD1 antigens and PPD corrected for pre-ART CD4(+) T cell counts were higher at all time points in individuals with ART-associated tuberculosis (P<.001) and were associated with areas under receiver operator characteristic curves of 0.90 for RD1 (95% confidence interval [CI], 0.78-1.00) and 0.92 for PPD (95% CI, 0.83-1.00) for the diagnosis of ART-associated tuberculosis. Pre-ART IFN-gamma responses enabled stratification of participants into groups with risks of subsequent tuberculosis of 0.7%, 9.3%, and 30.0%. Type 1 effector T cell responses are prominent in ART-associated tuberculosis, but additional immune defects may be more important in paradoxical TB-IRIS. IFN-gamma release assays may contribute to the prediction and diagnosis of tuberculosis during early ART.

Unmasked Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Disease: A Disease Spectrum after Initiation of Antiretroviral Therapy

Antiretroviral therapy (ART) has beneficial effects on mortality and lowers the incidence of diseases caused by opportunistic infections, such as tuberculosis (TB). Although ART has sustained long-term benefits, the risk of TB is high during the first 3 months after ART initiation. Among cases of ART-associated TB, we define "unmasked TB" as that which occurs in patients with reactivation disease who develop clinically recognizable TB after ART with the restoration of previously acquired TB antigen-specific functional immune responses. TB cases with clinical evidence of an inflammatory syndrome are a subset of these unmasked cases, which we define as "unmasked TB-immune reconstitution inflammatory syndrome." With more widespread use of ART in areas with a high prevalence of TB, unmasked TB will likely become more common. TB diagnostics with improved sensitivity and specificity are urgently needed to detect subclinical TB before it is unmasked.

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

Immune Reconstitution and “Unmasking” of Tuberculosis during Antiretroviral Therapy

Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease-a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as "unmasking"), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term "ART-associated TB" be used to refer collectively to all cases of TB presenting during ART and that "immune reconstitution disease" be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease.